Introduction: Therapeutic apheresis effects on medications

AABB/ASFA Joint Session

Suzanne Thibodeaux, MD PhD Assistant Professor Department of Pathology and Immunology Washington University in St. Louis

October 14, 2018 Financial disclosures

None

www.aabb.org 2 Learning objectives By the end of the talk, the audience should be able to:

1. Describe the basic principles of therapeutic apheresis

2. Identify apheresis attributes that may affect medication levels

3. Identify patient attributes that may affect medication levels

www.aabb.org 3 www.aabb.org 4 https://www.google.com/search?q=apheresis&ie=utf-8&oe=utf-8&client=firefox-b-1-ab What is apheresis?

According to the American Society for Apheresis

A procedure in which blood of the patient or donor is passed through a medical device which separates one or more components of blood and returns the remainder with or without extracorporeal treatment or replacement of the separated component.

5 Schwartz, et al. Journal of Clinical Apheresis 31:149–162 (2016) Where did apheresis come from? Cream separators and computer companies! 1870s 1940s-1950s 1960s

Cream separator - hand-cranked WW2 – isolation of serum albumin IBM –development of automated continuous centrifugation fraction from plasma, other apheresis, IBM 2990 separation of blood components

Dr. Karl de Laval Dr. Edwin Cohn George Judson

http://worldapheresis.org/wp-content/uploads/2015/07/CDLposter.png; https://www-03.ibm.com/ibm/history/exhibits/healthcare/healthcare_08.html The apheresis circuit is continuous

Adapted from: Williams ME, Balogun RA. Clin J Am Soc Nephrol. 2014;9(1):181-190. Apheresis separates whole blood into its components

Specific gravity Blood Component <1.025 Density Plasma 1.030 Plasma Platelets WBC RBC 1.035

1.040 Platelets

Plasma Density 1.045 Immature hematopoietic cells 1.050 T cells Platelets 1.055 Lymphocytes Plasma 1.060 B cells Promyelocytes 1.065 WBC Monocytes WBC 1.070 Myelocytes, Basophils

1.075 Band and Segmented Neutrophils

RBC RBC Reticulocytes 1.080

1.085

1.090 Erythrocytes

1.095

>1.100 https://www.terumobct.com/Public/306670988.pdf 8 Araujo AB, et al. Cytotherapy. 2017 Jan;19(1):128-130.; Keever-Taylor C, et al. Blood 2014 124:3850; Adapted from: Linz, W. et al. (2014). Principles of Apheresis Technology (5th ed.) Vancouver, British Columbia: ASFA. Apheresis =/ Hemodialysis

Arterial Venous inflow return Membrane

Dialysate Dialysate outflow inflow

https://www.niddk.nih.gov/health-information/kidney-disease/kidney-failure/hemodialysis https://www.uptodate.com/contents/overview-of-the-hemodialysis-apparatus?source=search_result&search=hemodialysis&selectedTitle=1~150 Learning objectives By the end of the talk, the audience should be able to:

1. Describe the basic principles of therapeutic apheresis Apheresis allows density-based separation of blood into components that can then be removed/replaced

2. Identify apheresis attributes that may affect medication levels

3. Identify patient attributes that may affect medication levels

www.aabb.org 10 Apheresis enables removal or exchange of selected blood components Specific gravity Blood Component <1.025 Plasma Plasma Exchange 1.030 Adsorption, 1.035 LDL apheresis 1.040 Platelets Plateletpheresis

1.045 Immature hematopoietic cells 1.050 T cells 1.055 Plasma Lymphocytes 1.060 B cells Leukapheresis Promyelocytes 1.065 WBC Monocytes 1.070 Myelocytes, Basophils Extracorporeal

1.075 Band and Segmented Neutrophils photopheresis RBC 1.080 Reticulocytes

1.085 Red Blood Cell 1.090 Erythrocytes exchange 1.095

>1.100 11 Araujo AB, et al. Cytotherapy. 2017 Jan;19(1):128-130.; Keever-Taylor C, et al. Blood 2014 124:3850; Adapted from: Linz, W. et al. (2014). Principles of Apheresis Technology (5th ed.) Vancouver, British Columbia: ASFA. Schwartz, et al. J Clin Apheresis 31:149–162 (2016) 12 Araujo AB, et al. Cytotherapy. 2017 Jan;19(1):128-130.; Keever-Taylor C, et al. Blood 2014 124:3850; Adapted from: Linz, W. et al. (2014). Principles of Apheresis Technology (5th ed.) Vancouver, British Columbia: ASFA. Kinetics of antibody removal during therapeutic plasma exchange 100 Before 80 After 60 40 20 0 Percent antibody antibody remaining Percent 1 2 3 4 Number of Plasma exchanges

Roman PEF, et al. Curr Opin Anesthesiol 2014, 27:57–64. Adapted from: Kaplan AA. Am J Disease 2008; 52:1180-96. Immune Adsorption and LDL apheresis

Antibody or LDL Adsorption column

www.aabb.org 14 https://www.accessdata.fda.gov/cdrh_docs/pdf12/H120005C.pdf. https://www.therapeutic-apheresis.com/en/therapies/immunoadsorption/. Schwartz, et al. J Clin Apheresis 31:149–162 (2016) 15 Araujo AB, et al. Cytotherapy. 2017 Jan;19(1):128-130.; Keever-Taylor C, et al. Blood 2014 124:3850; Adapted from: Linz, W. et al. (2014). Principles of Apheresis Technology (5th ed.) Vancouver, British Columbia: ASFA. Schwartz, et al. J Clin Apheresis 31:149–162 (2016) 16 Araujo AB, et al. Cytotherapy. 2017 Jan;19(1):128-130.; Keever-Taylor C, et al. Blood 2014 124:3850; Adapted from: Linz, W. et al. (2014). Principles of Apheresis Technology (5th ed.) Vancouver, British Columbia: ASFA. Schwartz, et al. J Clin Apheresis 31:149–162 (2016) 17 Araujo AB, et al. Cytotherapy. 2017 Jan;19(1):128-130.; Keever-Taylor C, et al. Blood 2014 124:3850; Adapted from: Linz, W. et al. (2014). Principles of Apheresis Technology (5th ed.) Vancouver, British Columbia: ASFA. Apheresis enables removal or exchange of selected blood components Specific gravity Blood Component <1.025 Plasma Plasma Exchange 1.030 Adsorption, 1.035 LDL apheresis 1.040 Platelets Plateletpheresis

1.045 Immature hematopoietic cells 1.050 T cells 1.055 Plasma What aboutLymphocytes 1.060 B cells Leukapheresis Promyelocytes 1.065 WBC Monocytes 1.070 Myelocytes, Basophils Extracorporeal

1.075 Band and Segmented Neutrophils photopheresis RBCmedications?! 1.080 Reticulocytes

1.085 Red Blood Cell 1.090 Erythrocytes exchange 1.095

>1.100 18 Araujo AB, et al. Cytotherapy. 2017 Jan;19(1):128-130.; Keever-Taylor C, et al. Blood 2014 124:3850; Adapted from: Linz, W. et al. (2014). Principles of Apheresis Technology (5th ed.) Vancouver, British Columbia: ASFA. Learning objectives By the end of the talk, the audience should be able to:

1. Describe the basic principles of therapeutic apheresis Apheresis allows density-based separation of blood into components that can then be removed/replaced

2. Identify apheresis attributes that may affect medication levels Apheresis can have varying effects on remove blood components and medications within a given layer

3. Identify patient attributes that may affect medication levels

www.aabb.org 19 Patient factors with potential effects on apheresis and medications Apheresis Medications Patient size/plasma volume Determines amount of replacement fluid used May determine dosing Adjustment of weight-based BMI/amount of adipose tissue Adjustment of calculations dosing Dictates frequency, duration, replacement Disease requiring apheresis Disease-specific medications fluid used, amount processed, etc. May affect anticoagulant used, replacement Comorbidities dose adjustments fluid, replacement volume Clinical status May affect replacement fluid, access Altered metabolism Hypalbuminemia – may affect Nutritional status Hypoalbuminemia, electrolyte abnormalities protein-bound drugs

www.aabb.org 20 Learning objectives By the end of the talk, the audience should be able to:

1. Describe the basic principles of therapeutic apheresis Apheresis allows density-based separation of blood into components that can then be removed/replaced

2. Identify apheresis attributes that may affect medication levels Apheresis can have varying effects on remove blood components and medications within a given layer

3. Identify patient attributes that may affect medication levels Patient factors can influence both apheresis and medications, and the intersection between can be complex

www.aabb.org 21 Thank you!

www.aabb.org 22 Anticoagulants & Apheresis: The Lab Medicine & Blood Bank Perspective

Christopher A. Tormey, MD Associate Professor of Laboratory Medicine Yale University School of Medicine VA Connecticut Healthcare System October, 2018 Talk Outline

 Discussion of the various types of anticoagulation, their mechanism of action, basic lab monitoring, and half-lives

 Also discuss ‘safe’ hold periods prior to central line placement for non-urgent procedures  Review of how apheresis-related care (particularly plasma exchange) is impacted by these various forms of anticoagulation from the BB perspective

 Removal + considerations for replacement fluids Anticoagulants: Overview on Mechanism of Action

 Anticoagulants, which exploit the mechanisms of normal hemostasis, come in essentially one of four varieties:

 Agents to induce factor depletion Focus on  For example, warfarin these classes for  Agents that inhibit coagulation factor activity today’s talk  For example, heparin

 Agents that inhibit PLT function  For example, aspirin

 Clot ‘busters’  For example, tissue plasminogen activator (tPA) Yale-VA CT IR BB Guideline FACTOR DEPLETION Warfarin Anticoagulation

 Following the ingestion of warfarin, a vitamin K antagonist (VKA), all vitamin K dependent factors will begin to decrease  fVII = most sensitive to warfarin therapy because of it’s very short in vivo half-life (4-6 hours)  Anticoagulant effect may not be seen until several doses (or until many hours after dosing)  Since fVII is very sensitive to warfarin, we use the PT to gauge efficacy of therapy  Goal PT = 1.5-2x upper limit of normal for most hypercoagulable or treated patients  Equates to INRs of 2.0-3.5

Rose DK, et al. J Stroke Cerebrovasc Dis 2018; 27:2049 Warfarin: Half-Life & Hold Times  Concepts of half-life & VD are not completely applicable to warfarin

 Since it induces changes in factor levels slowly over time, which themselves all have different half-lives  For non-urgent apheresis line placement, hold times of 4-5 days recommended

 For urgent apheresis line placement, use of 4F- PCC for reversal recommended

Rose DK, et al. J Stroke Cerebrovasc Dis 2018; 27:2049 Unold D, et al. Arch Pathol Lab Med 2015; 139:1568-75. Apheresis & Warfarin Anticoagulation: General Considerations  Removal:

 Few large scale studies examining warfarin removal by apheresis  One study showing pre-INR predictive of post-TPE-INR (with albumin only used as replacement)  Replacement fluid:

 For therapeutic INRs, a recent survey indicated most apheresis practitioners would use either albumin alone (45%) or albumin + plasma (36%)

 For super-therapeutic INRs, same survey indicated most would albumin + plasma (46%) or plasma alone (19%)

Zantek ND, et al. J Clin Apher 2014; 29:75-82. Cheng C, et al. Am J Clin Pathol 2017; 148:190-8. Shunkwiler SM, et al. J Clin Apher 2017; 33:371-9. Zantek ND, et al. J Clin Apher [Epub ahead of print] FACTOR INHIBITORS Factor Inhibition: Overview

 Unlike the factor depletion category where there is essentially one option (warfarin), there are numerous ways to inhibit coagulation factors  We’ll divide these into categories in the following slides (typically based on the site of action of the anticoagulant) Unfractionated Heparin & Related Anticoagulants Unfractionated Heparin

Heparin promotes anticoagulation by enhancing the activity of antithrombin (AT), a natural anticoagulant

It acts on multiple coagulation factors via AT, exerting most of its effects on FXa and FIIa

Half-life = ~45-60 min Unfractionated Heparin

 Following the administration of heparin, the activity of antithrombin is immediately enhanced

 Anticoagulant effect immediately observed  Since heparin primarily affects fX activity, we use the aPTT to gauge efficacy of therapy

 Goal PTT = 1.5-2x upper limit of normal for most hypercoagulable patients  Can also use the anti-Xa assay with goal ~0.3-0.7 IU/mL

 This assay has replaced PTT at my VA facility for heparin monitoring

https://www.thrombosisadviser.com/heparins/ Low molecular weight heparins (LMWHs)

 LMWHs also work primarily via enhancement of antithrombin (AT) to exert anticoagulant effects on FXa and FIIa

 Their effect on FXa >>> FIIa  Commonly used LMWHs:

 Enoxaparin (Lovenox) with half-life of ~4-6 hours

 Dalteparin (Fragmin) with half-life of ~3-5 hours  LMWHs are only monitored with the anti-Xa assay (they have no impact on PTT)

Hirsch J. Circulation 1998;98:1575-82. Holding Before Line Placement vs Active Reversal

• For active reversal in an urgent setting, PROTAMINE is preferred! • Advise providers that FFP/plasma can make PTT prolongation worse via antithrombin supplementation Apheresis & UFH/LMWH Anticoagulation: General Considerations

 Removal:

 Data from large studies are lacking for unfractionated heparin & LMMHs

 One study of 15 TPEs in pts on continuous heparin infusion found significant removal of heparin by plasma exchange  Therefore, supplementation or close monitoring of PTTs and/or anti- Xa may be warranted in UFH patients  Replacement fluid:

 No consensus; recent survey indicated most apheresis practitioners would use either:  Albumin alone (35/52%, UFH/LMWH) or,  Albumin & plasma (32/25%. UFH/LMWH) when UFH or LMWH is in therapeutic range

Shunkwiler SM, et al. J Clin Apher 2017; 33:371-9. Cheng C, et al. Am J Clin Pathol 2017; 148:190-8. Zantek ND, et al. J Clin Apher [Epub ahead of print] Direct Xa Inhibitors Direct Xa inhibitors: Brief background  Relatively new class of anticoagulants which inhibit FXa, a potent procoagulant in the common pathway

 Known as ‘xabans’ as all end with this term  These drugs include:

 Rivaroxaban (Xarelto)

 Apixaban (Eliquis) Oral with half-lives of ~6-20 hours  Edoxaban (Savaysa)

 Betrixaban (Bevyxxa)

Dobesh PP, et al. Drug 2015;75:1627-44. Chan NC, et al. Vasc Health Risk Manag 2015;11:343-51. An Aside About Fondaparinux

 Fondaparinux (Arixtra) is an oddball anticoagulant

 ‘Synthetic’ drug very similar to LMWHs as is injected, has a half-life of 17-21 hrs, works via antithrombin & can be monitored by modified anti-Xa assays

 But!

 Exerts near-exclusive effects on FXa (unlike LMWHs which act on FXa and to a lesser extent FIIa)  CANNOT be reversed by protamine

 Therefore, is something of a hybrid between oral anti- Xa drugs and LMWHs

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000403/WC500027736.pdf https://www.sciencedirect.com/topics/neuroscience/fondaparinux Anti-Xas: Site of action in the coagulation cascade

Site of action; inhibits the common coagulation pathway

Act primarily by binding FXa active site (exception = fonda, which acts via AT) Hold Times & Reversal of Anti-Xas

 Currently, some major issues with these drugs for peri- procedural concerns

 Relatively long half-life

 There is NO acute care monitoring test generally available at most facilities  PT/PTT are INSENSITIVE to these agents  Reference labs offer send out for modified anti-Xa assays

 There is no currently available antidote or direct reversal agent**  Note that protamine does not work for any of these drugs (including fondaparinux)  Therefore, for non-urgent line placement, hold times of 24-48 hrs are recommended

Dobesh PP, et al. Drug 2015;75:1627-44. Chan NC, et al. Vasc Health Risk Manag 2015;11:343-51. An Antidote to FXa Inhibitors: Applicable to Urgent Line Placement

 Andexanet alfa (AndexXa)

 A modified, recombinant version of FXa  Serves as a ‘decoy receptor’ for FXa inhibitors  Has a high affinity for these drugs  Should be able to outcompete endogenous FXa

 Approved in May, 2018  Hopefully coming soon clinically; will be initially rolled out to ~40 major trauma centers (late 2018) & then generally available (sometime in 2019)  Expensive!  ~$55-60,000 / reversal episode  Until available, may consider a low-dose of 4F-PCC for urgent reversals…

Husted S, et al. Drug Saf 2016;39:5-13. Siegal DM, et al. NEJM 2015;373:2413-24. Connolly SJ, et al. NEJM 2016;375:1131-41. Apheresis & Non-heparin Xa Anticoagulation: General Considerations

 Removal:

 Extremely limited practical data in this area

 80-95% plasma binding suggests likely removal by TPE  Could be considered as ‘last resort’ in OD  One case of this reported for apixaban; essentially no other data  Replacement fluid:

 Not directly asked in recent survey

 Authors note that replacement fluid regimens ranged from no change in practice  some/all plasma; no consensus listed

Lam MW, et al. Texas Heart Institute Journal 2015; 42: 377-80. Shunkwiler SM, et al. J Clin Apher 2017; 33:371-9. Cheng C, et al. Am J Clin Pathol 2017; 148:190-8. Zantek ND, et al. J Clin Apher [Epub ahead of print] Direct Thrombin Inhibitors Direct thrombin inhibitors: Brief background  Relatively new class of anticoagulants which bind to thrombin (FIIa), a potent procoagulant in the common pathway  One of the earliest label indications for some DTIs was as an alternative to heparin

 Particularly useful in cases of heparin-induced thrombocytopenia (HIT)

 DTIs are now being expanded or proposed for other clinical settings  Anticoagulation for VTE, atrial fibrillation and even prevention of acute coronary syndromes

Di Nisio M, et al. NEJM 2005;353:1028-40. Ganetsky M, et al. J Med Toxicol 2011;7:281-7. DTIs: Site of action in the coagulation cascade

Site of action of DTIs; inhibits the common coagulation pathway

Act primarily by binding FIIa active site; also exhibit an anti-PLT effect (thrombin is a potent PLT agonist)

Di Nisio M, et al. NEJM 2005;353:1028-40. Ganetsky M, et al. J Med Toxicol 2011;7:281-7. DTIs: Facts and figures

 Commonly used DTIs include:

 Bivalirudin (Hirulog)

 IV route; 25 min t1/2; renal excretion and hepatic clearance

 Argatroban (Novastan)

 IV route; 45 min t1/2; primarily hepatic clearance

 Dabigitran (Pradaxa)

 Oral route; 12 hr t1/2; renal excretion

Di Nisio M, et al. NEJM 2005;353:1028-40. Ganetsky M, et al. J Med Toxicol 2011;7:281-7. Hold Times & Reversal of DTIs

 Like anti-Xas, some major issues with these drugs for peri-procedural concerns, particularly oral DTIs

 Relatively long half-life for dabigatran

 There is NO acute care monitoring test generally available at most facilities for oral formulations  PT/PTT are INSENSITIVE to these oral DTI agents  Therefore, what are current recommendations for DTIs re: hold times for line placement? Holding Before Non-Urgent Procedures

 For IV formulations, typically ok to perform procedures once PTT is <40 seconds

 Relatively short half-lives, similar to the approach to heparin  For oral formulations like dabigatran, consider at least 24-48 hours hold if normal renal function

 Holds of 2-6 days needed for those with renal impairment (2-4 days for CrCl <50; 4-6 days for CrCl <30) Antidote for Oral DTIs: Useful for Urgent Line Placement

 As of October, 2015 the FDA has approved a reversal agent for dabigatran

 Idarucizumab (Praxbind)

 MOAB fragment which binds and clears unbound dabigatran

 Drug widely available in most hospital pharmacies

 Tell your clinicians to call pharmacy if they’re seeking dabigatran reversal!

 Praxbind not applicable to other DTIs

 May try a low-dose of 4F-PCC for those…

http://reference.medscape.com/drug/praxbind-idarucizumab-1000042#5 Apheresis & DTIs: General Considerations  Removal:

 Extremely limited practical data in this area

 Like anti-Xas, protein binding suggests likely removal by TPE  Could also be considered as ‘last resort’ in OD  Hemodialysis much preferred for renally-cleared agents  Replacement fluid:

 Not directly asked in recent survey

 Authors note that replacement fluid regimens ranged from no change in practice  some/all plasma; no consensus listed Shunkwiler SM, et al. J Clin Apher 2017; 33:371-9. Cheng C, et al. Am J Clin Pathol 2017; 148:190-8. Zantek ND, et al. J Clin Apher [Epub ahead of print] Summary

 There are a variety of anticoagulants that work on numerous aspects of the coagulation system  Knowledge of their mechanisms / half-lives can help inform reversal and safe times for line placement & procedure performance  More large-scale study data are needed on practical aspects regarding removal of these agents by TPE as well as replacement fluid

 Until then, consensus approaches are helpful! Thanks for your time!

VA Connecticut Yale-New Haven Hospital

Yale School of Medicine The Effect of Apheresis on Medications: A Review (AABB/ASFA Joint Session)

10/14/2018 Faculty Disclosures

The following faculty have no The following faculty have a relevant financial relationships to relevant financial relationship: disclose: – Tina Ipe – Christopher Tormey MD Cerus Corporation: – Suzanne Thibodeaux MD, Grant/Research Support PhD Terumo BCT: Grant/Research Support

www.aabb.org 2 Learning Objectives

• Review apheresis modalities and its physiology as it pertains to medication interaction and clearance • Describe the effect of therapeutic apheresis on the pharmacokinetics of different drugs • Discuss strategies for appropriate drug management • Review anticoagulants and their effects on apheresis treatment

www.aabb.org 3 What Everyone Needs to Know About Medications and Their Removal with Apheresis

Tina S. Ipe, MD, MPH

October 14, 2018 I have no relevant financial relationships to disclose.

• Here are some disclosures you should know about: • I am not a pharmacist. • I may or may not be able to pronounce all the drug names appropriately.

www.aabb.org 2 Learning Objectives

• Review management of medications during overdose/ poisoning and envenomation • Review medication factors that impact their removal by therapeutic apheresis modalities • Determine appropriate dosing and timing of medications during apheresis

www.aabb.org 3 Case Report

• 45 year-old-male with nausea, vomiting, lethargy, severe headaches and clamminess. • Patient was confused, non-verbal and unable to follow commands. • PMH notable for renal and pancreatic transplant. • CSF fluid analysis showed elevated WBC, total protein count and yeast forms on India ink smear. • He was diagnosed with cryptococcal meningitis. • Prescribed liposomal amphotericin B at 5 mg/kg/day. • Received amphotericin B DOC at the same dosage.

Monroig-Bosque P del C, Ipe TS. The utility of therapeutic plasma exchange for amphotericin B overdose. Transfusion and Apheresis Science. https://doi.org/10.1016/j.transci.2018.09.015. Patient’s Renal Function

Monroig-Bosque P del C, Ipe TS. The utility of therapeutic plasma exchange for amphotericin B overdose. Transfusion and Apheresis Science. https://doi.org/10.1016/j.transci.2018.09.015. Assessment of Risk

• Stabilize patient • ABC (Airwary, Breathing, Circulation) • Consider supportive measures • Gastrointestinal decontamination • Emesis, oral activated charcoal • Diuresis, acid or alkaline • Antidotes • N-acetylcysteine, naloxone, flumazenil, anti-venom • Risk assessment • Extracorporeal methods • Hemodialysis, hemoperfusion, therapeutic apheresis Literature Review • Only two case reports of amphotericin B DOC overdose treated with TPE. • Case report 1, patient received both hemodialysis and TPE. • Case report 2, patient treated with TPE because of suspicion for TTP. Results showed that amphotericin decreased by 40%. • Most of the literature on TPE for medication removal are case reports or case series on overdose situations. • Only 25% are formal pharmacokinetic trials that evaluate TPEs impact on drug disposition. • Often, the effect of TPE is determined after the patient has received other treatments (gastric lavage, urinary alkalination, hemodialysis etc). ASFA Guidelines

Modality Indication RCT CT CS CR Category Recommendation Grade Mushroom 0 0 11 4 II 2C poisoning (305) (4) TPE Envenomation 0 0 3 4 III 2C (77) (4) Drug 0 0 12 >50 III 2C overdose/poisoning (215)

• Amanita phalloides ingestion results in symptoms <23 hours • Envenomation symptoms is dependent on snake • Drug overdose has PK variables that must be evaluated Historical Trends of TPE Usage in Poisoning

(Exchange transfusion)

(Peritoneal dialysis) (Continuous Renal Replacement Therapy)

Mardini J et al. Case reports of Extracorporeal Treatments in Poisoning: Historical Trends. Seminars in Dialysis. 2014; 27(4): 402-406. Drug Pharmacokinetics

Route of Drug Systemic A D Target Tissues M Liver E Kidneys Administration Circulation Volume of Distribution (VD)

• Defined as a measure of apparent space throughout which a drug appears to be distributed

• Low VD means drug is primarily present in intravascular space • Low VD (<0.2 L/kg) drugs are easily removed by TPE • High VD means that more drug is distributed in other spaces than the intravascular space • Evaluate drug’s multi-compartment kinetics • Speed of inter-compartment transfer • Rebound Plasma Protein Binding Affinity

• Defined as the degree to which medications attach to proteins within the blood • Highly protein bound drugs (>80%) are easily removed by TPE • Drugs with increased drug-free fractions are NOT easily removed by TPE • Drug-free fractions are unbound to serum proteins • Intravascular drug concentration increases during overdose/poisoning  Free drug fraction increases  Toxicity Time Between Dose Administration and TPE Initiation

• Considered more important than protein binding or Vd • Drug levels removed were higher when TPE was initiated immediately after dose administration

• Influenced primarily by distribution half-life (t1/2 α) • Distribution half-life provides insight in the time needed for a compound to be fully distributed in the body • If drugs are given time to distribute fully, then the effect of therapeutic apheresis might be minimal Clearance Rates

• Decreased drug serum concentrations after TA may not be reflective of true TA clearance • Endogenous elimination • Drug concentration rebound • Methods that focus on TPE clearance without measuring drug plasmapheresate levels tend to over-estimate drug removal How to assess the amount removed? • The “Vancomycin” example Publications type/# of Endpoint Findings patients Case report (n=1)1 Reduction in serum Yes; ~ 49% reduction concentration Case report (n=1)2 Reduction in serum Yes concentration Case report (n=1)3 Reduction in serum Yes; ~ 27% reduction concentration Case report (n=1)4 Reduction in serum No concentration PK trial (n=12)5 Total body stores (derived No; 6.3% of total body from amount in waste stores plasma) PK=Pharmacokinetic

1Ann Pharmacother 2006;40:2279–2280. 2Ann Pharmacother 2001;35:1400–1402. 3Pharmacol Toxicol Slide borrowed from 1997; 81:245–246 . 4Ann Pharmacother 1996;30:1038. 5 Ann Pharmacother 1997; 31:1132–1136 Rami Ibrahim How to assess the amount removed? • The Vancomycin example: explanation

? Optimal

cut-off

Drug Serum Serum Drug Concentration

TPE Time

o The pitfalls of before/after TPE serum concentration evaluation: • It does not take into account post-redistribution from tissues

Overestimation of removal Slide borrowed from Rami Ibrahim Relation Between Drug Removed and Biologic Effect • Biologic effect may not be affected despite drug concentration decrease

• Rituximab binds CD20 surface marker expressed on B cells Relation between the amount removed and biologic effect: Monoclonal Antibodies - Rituximab

Distribution half-life (t1/2α )~1.5-3 days and elimination t1/2 of ~ 20 days Publications Time of rituximab Results dose from TPE Darabi K, et al. Am J Clin Pathol 24-36 hours CD19+ and CD20+ B-cells 2006;125:592–597 depressed; activity against TTP maintained McDonald V, et al. J Thromb 24 hours (?) Yes; ~70% Haemost 2010;8(6):1201-8 Scully M, et al. Blood At a minimum 4 CD19+ B-cells depressed; 2011;118(7):1746-53 hours ADAMTS13 activity increased and Anti-ADAMTS13 IgG decreased; appropriate hematologic response to TTP seen Puisset F, et al. Br J Clin 24-72 hours Yes; 47% - 54% (mostly with Pharmacol 2013;76(5):734-40 after the first session) Slide borrowed from Rami Ibrahim Other Drug Properties To Consider

• Molecular weight • Hydrophilic/phobic properties • Short half-lives (< 2 hours) • Rapidly metabolized • Example: Amphotericin B DOC • Molecular weight: 924 Da • Hydrophilic molecule Antibiotics and Antifungals

Medication Name PPB Vd (L/kg) Removal by TA

Tobramycin N/A N/A Removal significant if Gentamycin TPE initiated quickly Vancomycin after drug initiation Chloramphenicol N/A N/A Removed by TPE

Amphotericin B Removed by TPE

Cephalosporins 20 – 96% 0.1-0.3 Poorly removed by TPE

Acyclovir 15% 0.7 Poorly removed by TPE

• Drug removal was varied because of different PK characteristics

Cheng CW, Tormey CA et al. Therapeutic Plasma Exchange and Its Impact on Drug Levels. Am J Clin Pathol 2017; 148:190-198. Antiepileptics and Antihypertensives

Medication Name PPB Vd (L/kg) Removal by TA

Phenytoin 70-90% High Poorly removed by TPE Theophylline N/A N/A Poorly removed by TPE Phenobarbital 75-95% 0.6 Poorly removed by TPE Carbamazepine 70-80% 0.8-1.9 Poorly removed by TPE

Medication Name PPB Vd (L/kg) Removal by TA

Verapamil 90% N/A Removed by TPE Amiodarone >98% N/A Poorly removed by TPE but works in OD Digoxin 20-30% 5-8 Poorly removed by TPE

Cheng CW, Tormey CA et al. Therapeutic Plasma Exchange and Its Impact on Drug Levels. Am J Clin Pathol 2017; 148:190-198. Chemotherapy and Immunosuppressive Agents

Medication Name PPB Vd (L/kg) Removal by TA

Vincristine 50-80% N/A Removed by TPE

Medication Name PPB Vd (L/kg) Removal by TA

Tacrolimus 75-99% 0.85-65 Erythrocytopheresis Cyclosporine 75-99% 13 Erythrocytopheresis Mycophenolic acid >98% N/A Poorly removed by TPE

Prednisone/Prednisolone 90-95% 0.6-0.7 Poorly removed by TPE

Cheng CW, Tormey CA et al. Therapeutic Plasma Exchange and Its Impact on Drug Levels. Am J Clin Pathol 2017; 148:190-198. Monoclonal Antibody Therapies

Slide borrowed from Rami Ibrahim Drug Supplementation

Kale-Pradhan et al. Pharmacotherapy 1997; 17(4):684-695 Drug Side Effects Treated with TA

Kale-Pradhan et al. Pharmacotherapy 1997; 17(4):684-695 Case Summary

Monroig-Bosque P del C, Ipe TS. The utility of therapeutic plasma exchange for amphotericin B overdose. Transfusion and Apheresis Science. https://doi.org/10.1016/j.transci.2018.09.015. What Have We Learned?

• Drugs can be removed by therapeutic apheresis. • Many factors need to be taken into account when deciding to use therapeutic apheresis. • Volume of Distribution, Protein Binding, Clearance Rates etc. • Normal pharmacokinetics may not apply in situations of drug overdose. • If therapeutic effect of drugs need to maintained, drugs should be administered after the apheresis procedure and allow for maximal time between drug administration and the apheresis procedure. • More extensive studies using sound PK methodology need to be performed. References

• Ibrahim RB, Balogun RA. Medications in Patients Treated with Therapeutic Plasma Exchange: Prescription Dosage, Timing and Drug Overdose. Seminars in Dialysis. March-April 2012. 25(2): 176- 189. • Ibrahim RB et al. Drug Removal by Plasmapheresis: An evidence Based Review. Pharmacotherapy 2007; 27(11):1529-1549. • Ibrahim RB, Balogun RA. Medications and Therapeutic Apheresis Procedures: Are we Doing Our Best? Journal of Clinical Apheresis. 2013;28: 73-77. • Schutt et al. The role of Therapeutic Plasma Exchange in Poisonings and Intoxications. Therapeutic Apheresis for Nephrologists. Seminars in Dialysis. 2012; 25(2):201-206.